# Discrepancy in time for genetic differences between human and chimpanzee to accumulate

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Genetic differences between human and chimpanzee include ~50,000 amino acid changes, ~30,000,000 point mutations in non-coding sequences, and millions of insertions, deletions, inversions, genomic rearrangements, and transposable element movements [1]. The vast majority of these genetic changes are neutral [2] [3]. For neutral mutations, the expected number of generations required to reach fixation in the population is the reciprocal of the mutation rate per site per generation [4]. This holds irrespective of selection at other linked loci, changes in population size, or almost any other conceivable complication [4]. The human mutation rate, μ, is ~10-8 per site per generation [5]. Although μ can be orders of magnitude greater at certain sites, the fact that, as cited above, millions of neutral mutations occurred in the human line since its divergence from the chimpanzee line indicates that at least thousands of mutations occurred at the average rate of 10-8 per site per generation. Since the expected number of generations required for any one of these mutations to reach fixation in the population is the reciprocal of μ, this number equals ~108 generations. Since a generation is ~20 years for humans [5], the time required for any one of these thousands of neutral mutations to reach fixation is ~109 years.

According to the currently-known fossil record, the human line diverged from the chimpanzee line between 6 and 8 million years ago [7].

How is this major discrepancy between population genetics and the fossil record to be reconciled?

References

[1] Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69-87 (2005)

[2] Harris, E. E. Non-adaptive processes in primate and human evolution. Am. J. Phys. Anthropol. 143 (Suppl. 51), 13-45 (2010)

[3] Vallender, E. J., Mekel-Bobrov, N. & Lahn, B. T. Genetic basis of human brain evolution. Trends Neurosci. 31, 637-644 (2008)

[4] Lanfear et al, Population size and the rate of evolution. Trends in Ecology & Evolution, January 2014, Vol. 29, No. 1, Pages 33-42

[5] Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471-475 (2012)

[6] Walker, R. et al. Growth rates and life histories in twenty-two small-scale societies. Am. J. Hum. Biol. 18, 295-311 (2006)

[7] Levin, N. Annual Review of Earth and Planetary Sciences, 43: 405-429 (2015)

Good literature work here and good question +1! In short, your main mistake was that you based your calculations on a single site and not on the whole genome. More info below.

Genome-wide vs sites specific mutation rate

The statistic of $$10^8$$ generations that you computed is the average rate of fixation of new neutral mutations per site. As considered the genome-wide statistic between humans and chimpanzee, you have to scale your predictions up to the entire genome. There are about $$3 cdot 10^{9}$$ nucleotides in either the human of the chimp genome. That would result in a genome-wide mutation rate of $$U ≈ 2 * 10^9 cdot 10^{-8} = 20$$ (the two is because mammals are diploids). Hence, the rate of fixation of 0.05 generation.

So, the expected time it would take for $$30 cdot 10^6$$ new mutations to fix would be $$30 cdot 10^6 cdot 0.05 = 15 cdot 10^5$$ generations. Because, such mutation can happen in either lineage (humans or chimps), we have to divide this number of 2 leading to $$7.5 cdot 10^5$$. With a generation time of 20 years, that would take $$1.5 cdot 10^7$$ years or 15 million years.

15 million years? Why not 6-8 million years as expected from fossil records?

Most of the discrepancy is probably due to vague approximation made in the computation. For example, you assumed a mutation rate of $$10^{-8}$$ while in reality, the average mutation rate is rather twice as large (Nachman et al., 2000, Kong et al., 2012, Wang et al., 2012, Rahbari et al. 2016).

Doubling this mutation rate would divide by 2 our expectation of 15 million years leading to an expectation of 7.5 million years that perfectly match the fossil records!

There is however another source that may cause an overestimation of the time needed… You assumed the absence of incomplete lineage sorting or in similar words, you assumed that the standing genetic variance in the ancestral population negligibly affected divergence among the two lineages. However, these discussions are for another time!

## Differences between human and chimpanzee genomes and their implications in gene expression, protein functions and biochemical properties of the two species

Chimpanzees are the closest living relatives of humans. The divergence between human and chimpanzee ancestors dates to approximately 6,5–7,5 million years ago. Genetic features distinguishing us from chimpanzees and making us humans are still of a great interest. After divergence of their ancestor lineages, human and chimpanzee genomes underwent multiple changes including single nucleotide substitutions, deletions and duplications of DNA fragments of different size, insertion of transposable elements and chromosomal rearrangements. Human-specific single nucleotide alterations constituted 1.23% of human DNA, whereas more extended deletions and insertions cover

3% of our genome. Moreover, much higher proportion is made by differential chromosomal inversions and translocations comprising several megabase-long regions or even whole chromosomes. However, despite of extensive knowledge of structural genomic changes accompanying human evolution we still cannot identify with certainty the causative genes of human identity. Most structural gene-influential changes happened at the level of expression regulation, which in turn provoked larger alterations of interactome gene regulation networks. In this review, we summarized the available information about genetic differences between humans and chimpanzees and their potential functional impacts on differential molecular, anatomical, physiological and cognitive peculiarities of these species.

## What is Human Genome

The human genome is the collection of human DNA. Human genetics focuses on the nucleotide sequence of the human DNA revealed by the Human Genome Project (HGP) completed on 14th April 2003. Humans are the most developed members of the mammal order primate. Humans, gorillas, chimpanzees, bonobos, and orangutans are close relatives collectively called the great apes. Homo sapiens is the scientific name of humans. The human genome contains over 3 billion base pairs organized into 46 chromosomes: 22 autosomal and two sex chromosomes. <2% of the human genome contains coding DNA transcribed into mRNA. About 20,000 protein-coding genes are present in the human genome. 98% of it is noncoding DNA, which includes genes coded for tRNA and rRNA, pseudogenes, introns, UTR (untranslated regions of mRNA), regulatory DNA, repetitive DNA, and mobile elements. Though chimpanzees are one of the closest relatives of humans, chimpanzee genome contains 24 paired chromosomes. The human chromosome 2 is the result of the fusion of the ends of ancestral chromosome 2A and 2B. Additional 150,000 bp sequence presents at the site of fusion. Shown in figure 1 is the human chromosome 2 and the additional sequence. The additionally linked genes may copy from the p end of the chromosome 9.

Figure 1: Human Chromosome 2

There are six chromosomal regions in the human genome that had undergone a strong and coordinated selection over the past 250,000 years. Interestingly, at least one allele maker unique to the human lineage is present in each of the above-mentioned regions. FOXP2 gene and CFTR gene are such markers.

## How Are Humans Different from Other Great Apes?

O n October 23, 2017, at the Sanford Consortium for Regenerative Medicine in San Diego, California, the Academy, in collaboration with the Center for Academic Research and Training in Anthropogeny (CARTA), hosted the Morton L. Mandel Public Lecture on “How Are Humans Different from Other Great Apes?” The program, which served as the 2060th Stated Meeting of the Academy, included a welcome from Gordon N. Gill (University of California, San Diego School of Medicine Chair of the Academy’s San Diego Program Committee) and featured remarks from Pascal Gagneux (University of California, San Diego CARTA) on Genomics, Life History and Reproduction Fred H. Gage (The Salk Institute CARTA) on Genetics and Brain Development Margaret J. Schoeninger (University of California, San Diego CARTA) on Anatomy and Behavior and Ajit Varki (University of California, San Diego CARTA) on Common Disease Profiles. The following is an edited transcript of some of the presentations.

I t is a privilege and honor for an organization that is less than ten years old (namely, CARTA) to partner with one that originated before the U.S. Constitution was written (the American Academy of Arts and Sciences). A common theme supported by both organizations is the discovery and dissemination of factual knowledge. Time does not allow me to provide a description of the origins and goals of CARTA, so I will simply read our mission statement:

To use all rational and ethical approaches to seek all verifiable facts from all relevant disciplines to explore and explain the origins of the human phenomenon, while minimizing complex organizational structures and hierarchies, and avoiding unnecessary procedural complexities. In the process, train a new generation of scholars in anthropogeny [understanding the origin of humans], and also raise awareness and understanding of the study of human origins within the academic community and the public at large.

The overall question at hand today is: How Are Humans Different from Other Great Apes? At first glance, the last three words – “Other Great Apes” – may appear a bit strange. Let me explain. Humans are, of course, primates, who shared a common ancestor with Old World monkeys, then with Gibbons and other lesser apes, then with orangutans, followed by the gorilla and eventually with the common ancestor of the chimpanzee and bonobo, the so-called pygmy chimpanzee. Based on anatomical, physical, and behavioral features, we humans classified our closest evolutionary relatives as “the Great Apes.” In reality we are more similar at the genomic level to chimpanzees and bonobos than these two species are to gorillas. Moreover, at the genomic level, we are more similar to chimpanzees than mice and rats are to each other.

Thus, from a genomic perspective, humans are nothing more than one kind of “Great Ape” the correct term encompassing all these groups is “Hominid.” Asking how we are different from the other Hominids is one way to understand our own evolutionary origins, an approach that we call “Comparative Anthropogeny.”

Carrying out this comparison requires attention to a very large body of knowledge. One of the currently incomplete efforts of CARTA is to try to collate this knowledge on our website under the rubric of The Matrix of Comparative Anthropogeny (MOCA), which is a collection of comparative information regarding humans and our closest evolutionary cousins, with an emphasis on uniquely human features.

MOCA is still very incomplete, but it is organized by Domains (each with defined Topics) arranged by areas of interest and scientific discipline. Some examples of MOCA Domains are: Anatomy and Biomechanics, Behavior, Cell Biology and Biochemistry, Cognition, Communication, Culture, Dental Biology and Disease, Development, and Ecology. In the time available today, we cannot possibly cover even a small portion of these Domains of knowledge. Instead, our panelists will explore some specific examples of distinctly human features, ranging from genetic to cognitive to anatomical to behavioral to biomedical, while also considering implications for explaining human origins.

I would like to start with a little bit of geography. Humans are the only peri-planetary ape. In contrast to us, our closest living relatives are restricted to the tropical forests of Africa and Asia. As Ajit has just mentioned, we are more closely related to two species of these Great Apes. Some people have started debating whether we should be in the genus Pan or whether the two species of Pan should be in the genus Homo.

Paradoxically, the living apes, even though their populations are under very intense threat from deforestation and direct hunting, still contain more genetic variability than all seven billion humans on the planet today. The other striking contrast you might notice is that all the other apes, except us, exist in at least two different species, but there is only a single species of humans today that has colonized the entire planet.

Each of us, as long as we live, is a unique mosaic of a genome that consists of 46 pieces of chromatin, reshuffled from our parents. Each of your haploid genomes is about a meter long. So you have about two meters of DNA in each one of your cells. That sounds mighty short, but each meter contains three billion base pairs, and therefore we have two times three billion base pairs.

One of the ongoing research projects in many labs around the world is to identify differences in the genomes of hundreds of different apes and thousands of different humans, which are now available for study because the entire genome, each of the three billion base pairs, has been sequenced.

The results are showing some very surprising findings. There are huge differences in copies. For example, there are copies of segments that can range from a couple of base pairs to millions of base pairs that have expanded in only one species of ape, or in chimpanzees and gorillas, but not in humans. In the reverse, we have copies of chunks of DNA that have only expanded in humans but not in the other apes.

And there are completely novel genes that pop up in different species. There are pseudogenes that are still recognizable based on their DNA sequence, but have stopped encoding proteins. You can mine the genomic data to find evidence for recent positive selection, in which natural selection has forced more changes to the protein-coding DNA than you would expect.

Humans are made of trillions of cells, and different cell types play a different subroutine off the mostly clonal genome that is in all your cells. So by tweaking where you express which combinations of genes, you can actually change how the organism looks.

I thought I would say a few things about the complex nature of the genomic landscape. In these three billion base pairs, we have about twenty thousand protein coding genes, which corresponds roughly to the number of undergraduate students at USCD. There are hundreds of thousands of enhancers – chunks of DNA with a function, even though they never make proteins – that influence the activity of other genes. And many of these are transcribed. We don’t know what that transcription really does. So, we have a vast genomic landscape, and we are only beginning to discover new functions for pieces of DNA that, until recently, were thought of as mere junk.

One of the striking differences between humans and their closest living relatives is the schedule of life. In several aspects, humans have slowed down. Our gestation time is only slightly longer than that of the chimpanzees, for example, but we have invented a couple of key things. Humans seem to have invented childhood, adolescence, certainly grandmotherhood, and sometimes grandparenthood for relatively long periods – up to 30 percent of the total lifespan is comprised of the post-reproductive survival phase.

Some have proposed that this might have been an adaptation to cultural opportunities, given the importance of cultural transfer in our species. Or perhaps it was due to nutritional opportunities, in which mothers with better access to high density-rich foods can actually do novel things in utero. It may also have been facilitated by stronger pair bonds between parents or by allomothering, which is when other individuals in the group help you take care of your kids.

Now, what does this delay in growth allow? The delay allows increased transmission of behavior and concepts. Humans are eminent copiers. We hyper-imitate. In comparative studies of the transmission of tool use, chimpanzees are very good at imitating to achieve a goal. Humans, on the other hand, focus at least as much on how it is done and show normative tendencies.

Human minds are effective copying machines. Somebody comes up with a good idea, and then everybody in the group maintains that idea. We develop a ratcheting culture, in which we build upon each other’s ideas.

One very interesting idea is that this delayed development is actually a biological assimilation of the cultural input. Humans in hunter-gatherer societies have a shorter inter-birth interval than apes. Humans can give birth about every three years, chimpanzees only every five or more years. Even though our babies are costly, we can produce more of them than our living Great Ape relatives. And when humans are done making babies, they actually survive for a long time. Our societies, long before medicine, the Industrial Age, or the farming age, allowed for grandmothers and grandfathers.

Interestingly, in evolutionary biology it is pretty much accepted that toward the end of the reproductive period, there is a minimal force of selection. But if you allow for cultural transmission, post-reproductive individuals can actually facilitate the survival of related, younger individuals, which opens up later stages in life to the action of natural selection.

With regard to forming the next generation, what is striking is that to find strict monogamy in nonhuman primates, you need to look at the lesser apes, the Gibbons. They live only in the forests in Southeast Asia. The other Great Ape close relatives have completely different mating systems: for example, the gorilla’s harem-like societies, with the big Silverbacks that have exclusive access the dispersed systems of the orangutans, with two types of males: the big males that are chosen by the females and the younger males that bypass female choice and force the females to mate with them and chimpanzees and bonobos, with multi-male/multi-female societies, in which each ovulating female will mate with every male in the group.

For humans, what is striking is that even though humans live in groups, pair bonding is a major phenomenon. This allows humans to participate in reciprocal exogamy, which essentially means exchanging mates across social groups. It allows for linking multiple kin lineages. Now, if you combine the cognitive capacity of our slowly maturing children, the allomothering, and the input of the group into each child, a striking array of things becomes possible. It essentially allows for our social-cultural niche. We share symbols. We have personal names. We have kinship terms, which allows for the formation of tribes. We have shared rituals, dance and music, sacred spaces, and group identity markers, and we can increase the capacity to cooperate with and compete against other groups.

I would like to provide you with an example or two of how a process may have led to the differentiation of humans from our closest relatives, and then talk about a cellular system that allows us to look at potential molecular and cellular differences that might have led to dissimilarities in who we are.

What we know is that the brain has increased in size across species during evolution along the branch that leads to humans. And we have come to the hypothesis that the growth of the brain is causally linked to what it is to be human. The correlation is placed there because as the brain became larger, we acquired features that seemed more unique to the complexity in behavior that humans can exhibit. For example, when we think about what are the measures that allow us to examine how we may have evolved, we can use genetic information. Svante Pääbo has been able to extract DNA from ancient bones and make a hypothesis about how that DNA may differ through evolution, particularly from our closest ancestral relatives.

Sometimes we obtain postmortem brain tissue from our closest ancestral relatives. We can measure the magnitude of gyrations in the cortex and explore specific ideas or hypotheses about how they may be important. In addition, we have fossil crania to study and, from those skulls, we can build casts or make CT scans to get an idea of how the brain size was changing, again building our theories based on these measurements and the correlations that exist.

Furthermore, we have cultural icons as well that give us an idea of how far a species had emerged, given its ability to build, plan, and generate art.

In each case, we have material that we can work with: genetic material, tissues, organs, and cultural artifacts. What has been missing, however, is living tissue from some of our lost ancestors and from our closest relatives, like chimps and bonobos.

So the “missing link” is the ability to interrogate the activity and function of live cells and the phenotypes of the cells. We have established a bank of cellular tissues from many of our closest relatives that allows us to look at distinctions between ourselves and our closest relatives.

As Pascal mentioned, chimpanzees and bonobos are our closest relatives, with 95 percent of our genomes being similar yet, there are vast differences in phenotype. How can we begin to understand the cellular and molecular mechanisms responsible for these differences?

One of the things we can do is take somatic cells, such as blood cells or skin cells, from all of our closest relatives. Through a process called reprogramming – by overexpression of certain genes in these cells – we can turn the skin or somatic cell into a primitive cell, called an induced pluripotent stem (iPS) cell. These primitive cells are in a proliferating, living state that can be differentiated to form, in a dish, any cell of the body, allowing us, for the first time, to form living neurons or living heart cells from all of our closest relatives and then compare them across species.

These iPS cells represent a primitive state of development prior to the germ cell. So any change detected in these iPS cells will be passed along to their progeny through the germ cell and into their living progeny.

Now a little bit of a disclaimer for those of us who work in this field: these cells have limitations. They are cells in culture. We cannot really look at social experience, and their relevance to a living organism is oftentimes questionable.

But we can ask the question: are there differences that are detectable at a cellular and molecular level that help us understand the origin of humans? We have begun building a library with other collaborators around the world, and have reprogrammed somatic cells from many of these species into iPS cells. They retain common features of embryonic stem cells at the cellular level and they have the same genetic makeup as predicted based on the species.

In our first attempt to see if we could identify differences in these primitive cells, we did what is called a complete transcriptional (mRNA) analysis. If we compare the transcriptional genomes of chimpanzees and bonobos, there are very few differences. So we pooled all our animals together and compared that combined nonhuman primate group to the human group.

In analyzing these genomes, we detected two very interesting genes. One is called PIWIL2 and the other is called APOBEC3B. Why are we interested in these two proteins? These two proteins are active suppressors of the activity of what we call mobile elements, which are genetic elements that exist in all of our genomes. In fact, 50 percent of the DNA in human genomes is made up of these mobile elements (molecular parasites of the genome). So what are mobile elements? They are elements that exist in specific locations in the genome and, through unique mechanisms, they can make copies of themselves and jump from one part of the genome to another. Barbara McClintock discovered these elements through her work on maize.

Some of us study a specific form of mobile elements called a LINE-1 retrotransposon. They exist in thousands of copies in the genome, as a DNA that makes a strand of RNA and then makes proteins that binds back onto the RNA, helping the element copy itself. This combination of mRNA and proteins then moves back into the nucleus where the DNA resides and pastes itself into the genome at a new location.

These LINE elements continue to be active in our genome, and they are particularly active in neural progenitor cells. Thus, the reason for our interest in PIWIL2 and APOBEC3B is because it has been demonstrated that both of these proteins can suppress the activity of LINE-1.

Not only do humans make more of these proteins, but as an apparent consequence, the lower levels of these L1 suppressors in chimpanzees and bonobos means the L1 elements are much more active in chimpanzees and bonobos than in humans.

When searching the DNA libraries (genomes) that have been sequenced for chimps, bonobos, and humans, there are many more L1 DNA elements in the genomes of chimps and bonobos relative to humans.

This greater number of L1 elements in non-human primate genomes leads to an increase in DNA diversity and, thus, in the diversity of their offspring and potentially in their behavior. This led us to speculate that this decrease in genetic diversity that occurs in humans leads to a greater dependence on cultural adaptive changes to survive as a species rather than genetic adaptive changes. For example, if a virus were to infect a chimp or a bonobo population, in order for that species to survive it would require a member of the species with the genetic mutation that provided protection in some form from the virus. Humans do not wait for the mutation from a member of the species that would provide protection from the virus. We build hospitals, we design antibodies, we transmit our knowledge through cultural information (cultural evolution) rather than relying on genetics (genetic evolution) for the spread and the survival of the species.

I n the 1990s, my research group happened to discover the first known genetic difference between humans and chimpanzees. Because I didn’t know very much about our close evolutionary relatives, I took a sabbatical and went to the Yerkes National Primate Research Center to learn more about apes and chimpanzees. Given my medical background, I paid special attention to diseases, and I found that the Center was using Harrison’s textbook of Internal Medicine, which is the same textbook I had used for humans. And so I thought, well, they must be just like us. And, indeed, when I first looked at the major causes of death in adult captive chimpanzees, the number one killer was heart disease, heart attacks, and heart failure. Again, I thought, well, they are just like humans. But then when I started going over the textbook with the veterinarian, I noticed that not all the diseases were the same.

So the question arises: are there human-specific diseases? There are a few criteria for human-specific diseases: they are very common in humans but rarely reported in great apes, even in captivity and they cannot be experimentally reproduced in apes (in the days when such studies were allowed). The caveat, of course, is that reliable information is limited to data on a few thousand Great Apes in captivity. But these apes were cared for in NIH-funded facilities with full veterinary care – probably better medical care than most Americans get – and there were thorough necropsies.

As it turned out, I was even wrong about heart disease. It was not until my spouse and collaborator Nissi Varki looked at the pathology that she realized that while heart disease is common in both humans and chimpanzees, it is caused by different pathological processes. While a human heart can show coronary blockage that reduces blood flow to the heart and results in myocardial infarction, heart attacks, and heart failure, chimpanzees that died of “heart attacks” and “heart failure” had a completely different pathology. They developed massive scar tissue replacing their heart muscle, which is called interstitial myocardial fibrosis.

It turned out that the veterinarians were well aware of this, but had not reported it because they thought it wouldn’t be interesting because it was not like humans! There is now a special project called The Great Ape Heart Project, which is providing clinical, pathologic, and research strategies to aid in the understanding and treatment of cardiac disease in all of the ape species.

There are actually two mysteries to be solved: why do humans not often suffer from the fibrotic heart disease that is so common in our closest evolutionary cousins? They all can get it – the orangutans, gorillas, chimpanzees, bonobos – and we don’t. Conversely, why do the Great Apes not often have the kind of heart disease that is common in humans?

Nissi and I then worked with Kurt Benirschke and with others and wrote an article on the “Biomedical Differences Between Humans and Nonhuman Hominids: Potential Role for Uniquely Human Aspects of Sialic Acid Biology,” which focused somewhat on our own research on sialic acid biology.

We put together a list of candidates of human-specific diseases that meet the criteria I mentioned earlier, and myocardial infarction is number one. Malignant malaria is number two. In studies done from the 1920s to the 1940s, people actually did horrible two-way cross-transfusions between chimpanzees and humans infected or not infected with malaria, and there was no evidence of cross-infection. In fact, the parasites looked the same, but they were actually completely different.

More modern work done by Francisco Ayala and others showed that, in fact, P. falciparum arose from P. reichenowi by a single transfer from a Great Ape. Pascal Gagneux and I wrote an article that explains what might have happened. There are multiple forms of ape malaria that are mild throughout Africa. At some point, we escaped because of a change in the surface sialic acid molecule. One of them finally “figured out” how to bind to the sialic prominent in us, and that is now P. falciparum malaria.

Another candidate for human-specific diseases is typhoid fever. More horrible studies were done in the 1960s that showed that large doses of Salmonella typhi did not result in severe cases of typhoid fever in chimpanzees. Working with Jorge Galán and others we found that, in fact, what happened is that the typhoid toxin, which is the soluble molecule that really mediates the severe symptoms of typhoid fever, cannot bind to the chimpanzee cell surface. It can only bind to the human cell surface (again, because of the sialic acid difference between the species).

Another candidate is cholera, which is a major killer in humans. Robert Koch complained in 1884 that “. . . although these experiments were constantly repeated with material from fresh cholera cases, our mice remained healthy. We then made experiments on monkeys, cats, poultry, dogs and various other animals . . . but we were never able to arrive at anything in animals similar to the cholera process.”

So, Vibrio cholerae does not induce diarrhea in adult animals other than in humans and many people are trying to figure out why.

There are many other candidates for human-specific diseases. There is another set of diseases in which various bacteria carry out molecular mimicry, in which bacterial capsular polysaccharides mimic common motifs on sialoglycans of mammalian cells – like a wolf in sheep’s clothing.

Another difference is in carcinomas, cancers of epithelial origin. To date, no captive Great Apes have reported carcinomas of the esophagus, lung, stomach, pancreas, colon, uterus, ovary, or prostate. They do develop cancer in the hematopoietic system and elsewhere.

There are a few thousand Great Apes living in captivity, and living well into their fifties and sometimes into their sixties. So you would expect a few carcinomas based on the incidence in humans. Nissi and I wrote an article that reviewed the subject, and concluded that while relative carcinoma risk is a likely difference between humans and chimpanzees (and possibly other Great Apes), a more systematic survey of available data is required for validation of this claim.

Time does not permit me to talk about Alzheimer’s Disease, HIV, hepatitis B complications, muscular dystrophy, preeclampsia, frequency of early fetal wastage, frequency of premature labor and birth, and frequency of chronic female iron deficiency. But bronchial asthma is interesting. Great Apes don’t seem to get bronchial asthma, an extremely common disease in all human populations. I found this claim a little hard to believe until I came across a paper entitled “Eosinophilic Airway Inflammation in a Monkey.” The article concluded that the present case that was studied was “remarkable because there is a paucity of reports of naturally occurring allergic airway disorders in nonhuman primates.”

So we can draw several conclusions: 1) The disease profiles of humans and chimpanzees are rather different. 2) Chimpanzees are actually poor models of many human diseases. We should pay more attention to that. 3) Humans are likely to be poor models of many chimpanzee diseases. The ethics of research on Great Apes has shifted and changed for good reasons. Pascal and I wrote an article with Jim Moore in 2005 that suggested we should conduct research on Great Apes that follows principles as similar as possible to those accepted for human research. We also suggested that researchers should volunteer to be subjects in the same experiments!

But like all things human, there are always two extremes and the people in the middle do not necessarily get a say. And so the question is whether the current ban on chimpanzee research will do more harm than good. I personally think it will do more harm because chimpanzees would also benefit from more ethical studies of their own diseases. But that is where we stand right now.

## A New View of Human-Chimpanzee Genome Differences

Comparisons of the human genome and the newly completed draft of the chimpanzee genome have unearthed major differences between the patterns of large duplicated segments of DNA in the two species.

Comparisons of the human genome and the newly completed draft of the chimpanzee genome have unearthed major differences between the patterns of large duplicated segments of DNA in the two species. These segmental duplications—which straddle large stretches of DNA—appear to have had a significant impact in altering the genomic landscape of apes and humans.

The popular understanding of the genetic differences between chimpanzees and humans should be recast in light of the findings of major differences in segmental duplications, said the senior author of the study, Evan Eichler of the Howard Hughes Medical Institute at the University of Washington School of Medicine.

So when we talk about how similar chimps and humans are, we really need to be careful that we are referring to variation in the whole genome as opposed to just those single-base-pair changes.

The traditional comparison cited in textbooks is that the difference is 1.2 percent, based on variations in single base-pairs in gene sequences. “But our data on these duplications shows a 2.7 percent difference, base per base, between chimps and humans,” said Eichler. “So when we talk about how similar chimps and humans are, we really need to be careful that we are referring to variation in the whole genome as opposed to just those single-base-pair changes.”

Eichler led the research team which published the comparative genome analysis in the September 1, 2005, issue of the journal Nature . Their research article was one of several analyses that accompanied a report on the draft sequence of the chimpanzee genome. Eichler also participated in the chimpanzee genome project.

Eichler and his colleagues in Seattle collaborated with researchers from the University of Bari in Italy, the Max Planck Institute for Evolutionary Anthropology, the Washington University School of Medicine in St. Louis, Children's Hospital of Oakland Research Institute and the National Library of Medicine.

Duplications of extensive segments of DNA occur during the production of sperm or eggs because of a predisposition of certain sites along the chromosomes to undergo breakage and rearrangements, Eichler explained. The resulting segmental duplications are evolutionarily important because they give rise to extra copies of genes that allow evolution to more freely “experiment” with mutations that could give rise to new traits, said Eichler. However, they can also lead to some two dozen genetic diseases.

Comparative analysis of segmental duplications in humans and chimpanzees could give important insights into why such specific abnormalities tend to occur and when these events arose. “The chimp can provide us historical information about ancestral states of disease,” said Eichler. “We know that there are some disease `architectures' that are shared between chimp and human, so we know that is the ancestral state. But other predisposing structures have arisen only in the human lineage, so such comparisons can provide important information on the genetic histories of disorders and disease susceptibilities of the human species.”

In their analysis, the researchers mapped the draft chimpanzee sequence data onto the human genome sequence as a reference. With their comparative map, they used sophisticated computational analysis to distinguish three categories of segmental duplications—those found in humans but not in chimpanzees those found in chimpanzees but not in humans and those shared between humans and chimpanzees. The researchers looked for duplications greater than about 20,000 base pairs in length.

Their analysis revealed that about a third of the duplications were found in humans but not in chimpanzees. “This was surprising, because it tells us that there is a high frequency of de novo duplications that arose over the time of human and great ape evolution,” said Eichler. “In contrast there are a lot of theories out there that duplications emerge and are maintained through selection or other processes such as gene conversion.”

In analyzing the chimpanzee-only duplications, the researchers found that chimpanzees showed fewer sites of duplication than humans, but they did have a great number of copies of the duplicated segments. Of particular interest to the scientists, was that a few of the shared duplications were often “hyperexpanded” in the chimpanzee.

In one of the more extreme cases, while the human genome showed four copies of one segment, the chimpanzee genome showed some 400 copies. “Such hyperexpansions are interesting because they occur on the ends of chromosomes,” said Eichler. “In the case of the segment that showed such massive duplication, it occurred near a region that in the great apes is broken into two chromosomes, but in humans is the fused chromosome two.” Such a difference hints at some chromosomal instability in both species that resolved itself differently in humans than in chimpanzees, he said.

Eichler was also intrigued by the data indicating that chimpanzee-only or human-only duplications tended to occur near regions of shared human-chimpanzee duplications—a phenomenon the researchers dubbed “duplication shadowing.” Discovery of this phenomenon, he said, could lead to greater understanding of the properties of chromosomal regions that tend to experience instabilities. “Such regions are pretty important from an evolutionary perspective, because a lot of people operate under the assumption that these types of mutational processes are randomly distributed,” said Eichler. “But in essence, they are not. There is probably something about these regions that has made them particularly hot in terms of change over the course of evolutionary time.”

The next major project the researchers will tackle is trying to understand what the differences in segmental duplication mean for the species in terms of the evolution of genes embedded in those segments. “At the top of our list is to work out which of the genes in the duplications show signatures of natural selection,” said Eichler. “This is a big question, because our hypothesis is that the big differences in structure between humans and chimps arose or might be tolerated because of important adaptations in the genes themselves.” There are a few examples of such rapidly evolving duplicated genes, but these genes have not been systematically analyzed due to the difficulties in characterizing genes in these regions of the genome.

When the genome of another great ape, the orangutan, is completely sequenced, the data should provide researchers with the opportunity to gain even more insight into evolutionarily important genetic differences between humans and other primates, he said.

Stop laughing. I know, my initial reaction too was, “really – it took genetics to tell us that?” But this is serious….really.

Males are 99.9% the same when compared to other males, and females are as well when compared to other females, but males and females are only 98.5% equal to each other – outside of the X and Y chromosomes. The genetic difference between men and women is 15 times greater than between two men or two women. In fact, it’s equal to that of men and male chimpanzees. So men really are from….never mind. It’s OK to laugh now…

We’ve been taught that other than X and Y, males and females are genetically exactly the same. They aren’t.

Does this matter? Dr. David Page, Director of the Whitehead Institute and MacArthur Genius Grant winner, says it absolutely does. He has discovered that both the X and Y chromosomes function throughout the entire body, not just within the reproductive tract.

In his words, “Humane Genome, we have a problem.” Medicine and research fails to take into account this most fundamental difference. We aren’t unisex, and our bodies know this – every cell knows it at the molecular level, according to Dr. Page.

For example, some non-reproductive tract diseases appear in vastly different percentages in men and women. Autism is found in 5 times as many males as females, Lupus in 6 times as many women as men and Rheumatoid Arthritis in 5 times as many women as men. In other diseases, men and women either react differently to disease treatment, react differently to the disease itself, or both. Dr. Page explains more and suggests a way forward in this short but very informative video.

David Page, Director of the Whitehead Institute and professor of biology at MIT, has shaped modern genomics and mapped the Y chromosome. His renowned studies of the sex chromosomes have shaped modern understandings of reproductive health, fertility and sex disorders.

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## Scientists home in on origin of human, chimpanzee facial differences

Common Chimpanzee in the Leipzig Zoo. Credit: Thomas Lersch/Wikipedia

The face of a chimpanzee is decidedly different from that of a human, despite the fact that the apes are our nearest relative in the primate tree. Now researchers at the Stanford University School of Medicine have begun to pinpoint how those structural differences could arise in two species with nearly identical genetic backgrounds.

The key lies in how genes involved in facial development and human facial diversity are regulated—how much, when and where the genes are expressed— rather than dissimilarities among the genes themselves. In particular, the researchers found that chimps and humans express different levels of proteins known to control facial development, including some involved in jaw and nose length and skin pigmentation.

"We are trying to understand the regulatory changes in our DNA that occurred during recent evolution and make us different from the great apes," said Joanna Wysocka, PhD, associate professor of developmental biology and of chemical and systems biology. "In particular, we are interested in craniofacial structures, which have undergone a number of adaptations in head shape, eye placement and facial structure that allow us to house larger brains, walk upright and even use our larynx for complex speech."

The researchers coined the term "cellular anthropology" to explain how some steps of early primate development can be mimicked in a dish, and thus used to study gene-expression changes that can shed light on our recent evolutionary past.

A study describing the research will be published online Sept. 10 in Cell. Graduate student Sara Prescott is the lead author. Wysocka and senior research scientist Tomasz Swigut, PhD, share senior authorship of the study.

The role of enhancer regions

For their comparison, the researchers focused on areas of DNA known as enhancer regions in human and chimpanzee genomes. These regions contain chemical tags and proteins bound to the DNA that control when, where and how nearby genes are expressed. Prescott and her colleagues wondered whether differences in the way proteins bind to these enhancer regions during development could explain morphological differences between humans and chimpanzees.

"We wanted to look at how the activity of these enhancer regions may have changed during recent evolution," said Wysocka. "Many recent studies have shown that changes in the DNA sequences of enhancers may mediate morphological differences among species."

To conduct the study, however, Prescott and her colleagues had to obtain a specialized type of cell present only in very early primate development. The cells, called cranial neural crest cells, originate in humans within about five to six weeks after conception. Although they first appear along what eventually becomes the spinal cord, the neural crest cells then migrate over time to affect facial morphology and differentiate into bone, cartilage and connective tissue of the head, and face.

"These cells are unique," said Prescott. "If we want to understand what makes human and chimp faces different, we have to look to the source—to the cell types responsible for making these early patterning decisions. If we were to look later in development or in adult tissues, we would see differences between the species but they will tell us little about how those differences were created during embryogenesis. But accessing early cell types like neural crest cells can be quite difficult, especially when studying primates."

To obtain this elusive cell type, the researchers used induced pluripotent stem cells, or iPS cells, made from chimpanzees. IPS cells, which are made from easy-to-obtain skin or blood samples, can be coaxed to become other tissues. Although iPS cells from humans have been well-studied, they've only recently been made from chimpanzees in the laboratory of Fred Gage, PhD, a professor of genetics at the Salk Institute for Biological Studies and a co-author of the study.

Prescott and her colleagues coaxed human and chimpanzee iPS cells to become cranial neural crest cells by growing them in the laboratory under a specific set of conditions. They then examined enhancer regions throughout the genome, looking for those that were not just active and therefore likely to be involved in craniofacial development, but also those whose patterns or degrees of activity seemed to vary between human and chimpanzee cells.

"Of course, humans and chimps are very closely related," said Wysocka. "Most of the regulatory elements are the same between the two species. But we did find some differences. In particular, we found about 1,000 enhancer regions that are what we termed species-biased, meaning they are more active in one species or the other. Interestingly, many of the genes with species-biased enhancers and expression have been previously shown to be important in craniofacial development or associated with normal intrahuman facial variation."

Snout length, shape and pigmentation

In particular, the researchers found that two genes, PAX3 and PAX7, known to affect snout length and shape in laboratory mice, as well as skin pigmentation, were expressed at higher levels in chimpanzees than in humans. Humans with less than the normal amount of PAX3 have a condition called Waardenburg syndrome, which includes craniofacial, auditory and pigmentation defects. Genomewide association studies in humans have identified PAX3 as a region involved in normal facial variation.

In contrast, another gene known to be involved in determining the shape of the beaks of finches and the jaw of a fish called a cichlid was expressed at higher levels in humans than in chimpanzees. In mice, overexpression of this gene, BMP4, in cranial neural crest cells causes a marked change in face shape, including a rounding of the skull and eyes that are more near the front of the face.

"We are now following up on some of these more interesting species-biased enhancers to better understand how they impact morphological differences," said Wysocka. "It's becoming clear that these cellular pathways can be used in many ways to affect facial shape."

## Conclusions

If humans evolved from chimps, why are there still chimps? The two major misconceptions this question reflects are that evolution is (1) always linear and (2) innately progressive. The common depiction of evolution as a linear progression throughout which ape-like creatures become more like modern humans is a gross simplification (see Gould, 1989, for further discussion of the iconography). Along these lines, we encourage educators to find images of human and ape family trees in which the human–chimp common ancestor is depicted as an illustration, rather than those that use photographs of chimps to represent this common ancestor – reinforcing the very misconception we are trying to avoid. As we discussed, much of evolution results in a pattern known as cladogenesis this involves processes that have given rise to the tree-like pattern of the diversity of life. Moreover, evolution does not necessarily equate to progress, as change is not always progressive (Ruse, 1996). It is incorrect to speak of living organisms as more (or less) evolved than other living organisms. Chimps are just as evolved as humans. The lineages leading to chimps and humans split from one another some 6 million years ago since then, each has taken its own path.

## Difference Between Human and Neanderthal

Human vs Neanderthal

The difference between humans and Neanderthals is their height, size and morphological features. Neanderthals, when compared to humans, were shorter in height and smaller in size. Humans have larger bodies when compared to Neanderthals, and have a significant difference in form and structure, especially in their skulls and teeth.

Another significant difference in the human and Neanderthal is their DNA. Fossil and archaeological evidence prove a distinct separation between Neanderthals and the modern Homo sapiens. Neanderthals were a different species to humans. The brain of a Neanderthal had a raised larynx, and was also bigger than that of the Homo sapiens.

There are notable physical differences between humans and Neanderthals, such as the Neanderthal has thicker bones, shorter limbs, an asymmetrical humerus, barrel chest and thicker metacarpals.

Neanderthal developmental differences from humans are the Craniodental development. Neanderthal and human faces and dental differences starts right from pre birth. The human and Neanderthal occurrence in time also signifies a difference in both species. Neanderthals, when compared to humans, were much stronger, and they lived in the cold climate of Europe.

Neanderthals were homogeneous species, and they are not human ancestors. Although, the difference between humans and Neanderthals when compared to apes is small. Neanderthals had a small population in the relatively recent past, and have no genetic or evolutionary connections with humans. Neanderthals displayed limited genetic diversity due to the lack of clear hybrids in the fossil record, and the lack of Neanderthal features in modern humans. Their limited genetic diversity suggests they went extinct, leaving no descendants. Their Homo erectus development is also more similar to that of apes rather than the modern human. The human child’s growth rate is slower than that of the Neanderthal child, as they used to grow rapidly from infants to adults.

Humans share similarities with other animals, such as anatomical, physiological and biochemical aspects. As humans are made from pre-existing material, as said by the bible, humans have much similarity within their basic body plan, the way it works and the underlying chemical pathway and machines in the body. They are almost the same as other mammals such as Neanderthals and other primates. Some of the significant differences between the human and Neanderthal are the distinctive sizes of their brain, bipedalism, decreased size of back teeth and advanced culture.

1. Human and Neanderthal brains and body structures have major differences in height and size.

2. Neanderthals are not ancestors of humans, but a homogenous species.

3. Humans have developed better eyesight, hearing or smell than Neanderthals due to skeletal adaptations.

4. Neanderthals and humans have many difference in their DNA.

5. Humans and Neanderthals seem not to have major differences in their behavior, and as well as cultural abilities, but Neanderthals fossil brains differ from the modern human brain.

So I note that the site self describes as a Pop Archaeology site, which is fair context but rubs me personally the wrong way even though the article lifted from Science Daily is fine in itself. Specifically the site is not sufficiently professional to lift photos from stock without checking their origin and relevance. I am no archaeologist but the photo labeled "The skeleton of a Neanderthal" looks entirely too well preserved and modern skeleton too me, besides the bronze arm ring complication.

Without taking the time to locate the original source who has been labeled "Neanderthal" in several stock data bases, I found a partial properly labeled "Exhumation" from mostly graveyards on Shutterstock [ https://www.shutterstock.com/search/exhumation https://www.shutterstock.com/sv/image-photo/skeleton-ancient-man-archaeo. ].

This may be an unfortunate mistake, but let us not make another one: I will likely not return here.

And it strikes me that my analysis was generic, while specifically chimps evolved in Africa while Neanderthals and Denisovans bot evolved in Asia/Europe.

The only way introgression would be possible is by the back flow of modern humans into Africa. That would mean a putative rather late (the last few thousand years), still localized and diluted introgression of such alleles which would be practically impossible to discover.

Not specifically alleles from those relatives, but I have seen attempt at estimating how long the populations in the chimp/human ancestral split interbred without finding much evidence either way.

There are - to my knowledge - no alleles that can be interpreted as a more modern interbreeding either way. The later human splits are 10 times younger, at some 0.5 Myrs vs 6 Myrs, and while it is an open question if we should consider them species (as most paleontologists seem to do) or subspecies the low introgression speak of incipient speciation. Pääbo was among the authors of a recent paper that used the two whole genome sequenced Neanderthals in a comparison test (since one is related to the human introgressions, the other not). They could show that the amount of Neanderthal DNA is the same 2.5 % or so all over, with the back flow into Africa likely screwing earlier assessments up to erroneously show differences across Asia,

So the interbreeding happened early when Africans left, but more importantly they see little signal of selection after the first 10 generations. I.e. the difference between population sizes would imply that we should see some 10 % Neanderthal alleles. But we see 1/4 of that due to "a species barrier" being in progress. That said, the fitness difference is not tremendous, it would suffice with 10 % lower progeny until the remaining alleles were too diluted (at 2.5 %) to matter. That is IIRC similar to what people see when some - but not all - mammal species are inbreeding but still technically the same species.

The point being that, besides the moral issues and despite the ability of especially plants and birds but also mammals to make hybrids long after speciation events, I would not expect to see such alleles as you ask about.

Neanderthal and Denisovan DNA have been found in human DNA. Has anyone looked at whether Neanderthal and Denisovan DNA been found in apes or chimps? If so, what were the results? I read that human DNA contains less than 4% Neanderthal DNA. Curious.