BOLA2 Copy Number Variation: Phenotype Effects From A Human Accelerated Region

Human Accelerated Regions (HARs) are regions of DNA that were conserved throughout prior (e.g., vertebrate) evolution but are significantly different in the human genome.

Allen Institute: ... of the known 3,171 human accelerated regions, 99 percent of these human-specific mutations fall into "non-coding" regions of DNA, or regions of DNA that don't contain instructions for making a protein. Many of them are in stretches of our genome known as enhancers, regions which regulate nearby genes, and about half of those are nestled in enhancers that are active in the developing human brain.

Our analysis of DNA regions used in predictors for common diseases and complex human traits found that large portions of phenotype variance reside in non-coding regions. This has important consequences for pleiotropy and for our understanding of genetic architecture. 

Regarding HARs, in a 2013 post Neanderthals Dumb? I wrote:

This figure is from the Supplement (p.62) of a recent Nature paper describing a high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression; see earlier post Structural genomic variants (CNVs) affect cognition.

From the Supplement (p.62):

Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.

Modern humans typically have many (e.g., 3-10) copies of BOLA2. In Neanderthals and apes, 2 copies. 

Variation in copy number presumably affects gene expression, even if the actual protein (coding base pairs) structure is not changed. There may be other mechanisms at work, of course.

Mutations in this 16p11.2 region are associated with schizophrenia, autism, brain size, reduced IQ, anemia, and other things. 

Since 2013 a number of papers have investigated the phenotype effects of BOLA2 copy number variation (CNV) and/or the 16p11.2 duplication/deletion. The latter is more complex as it affects multiple genes in addition to BOLA2. In the future, using whole exome or whole genome data in UKB, it should be possible to focus more specifically on effects of BOLA2 CNV.

For reference I note some of the results below.

Phenome-wide Burden of Copy-Number Variation in the UK Biobank (2019) 

16p11.2 C deletion: "We observe significant increases, on the order of one standard deviation, in weight, BMI, hip and waist circumference, reticulocyte count, and Cystatin C measures for these individuals. The larger 593 kb CNV associates with similar measures of body size and fat, as well as hypertension, diabetes/HbA1c, and abdominal hernia. These results are also indicative of effects due to developmental delay; namely, decreased measures of memory, higher Townsend deprivation (an index of material deprivation which considers employment, home/auto ownership, and household overcrowding in a person's neighborhood) ..."   

Note the effect sizes, e.g., on Townsend deprivation index, are extremely large, roughly 1 SD. The effect size for Prospective Memory score (related to ability to read, remember, and execute directions) is 2 SD!

 

 

Medical consequences of pathogenic CNVs in adults: analysis of the UK Biobank (2019)

Population percentage in parenthesis: 

See also:

The Human-Specific BOLA2 Duplication Modifies Iron Homeostasis and Anemia Predisposition in Chromosome 16p11.2 Autism Individuals (2019)

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study (2018)

The Inheritors and The Grisly Folk: H.G. Wells and William Golding on Neanderthals

Some time ago I posted about The Grisly Folk by H.G. Wells, an essay on Neanderthals and their encounters with modern humans. See also The Neanderthal Problem, about the potential resurrection of early hominids via genomic technology, and the associated ethical problems. 

The Grisly Folk: ... Many and obstinate were the duels and battles these two sorts of men fought for this world in that bleak age of the windy steppes, thirty or forty thousand years ago. The two races were intolerable to each other. They both wanted the eaves and the banks by the rivers where the big flints were got. They fought over the dead mammoths that had been bogged in the marshes, and over the reindeer stags that had been killed in the rutting season. When a human tribe found signs of the grisly folk near their cave and squatting place, they had perforce to track them down and kill them; their own safety and the safety of their little ones was only to be secured by that killing. The Neandertalers thought the little children of men fair game and pleasant eating. ...

William Golding was inspired by Wells to write The Inheritors (his second book, after Lord of the Flies), which is rendered mostly (until the end, at which point the perspective is reversed) from the Neanderthal point of view. Both Wells and Golding assume that Neanderthals were not as cognitively capable as modern humans, but Golding's primitives are peaceful quasi-vegetarians, quite unlike the Grisly Folk of Wells.

The Inheritors 

Golding considered this his finest novel and it is a beautifully realised tale about the last days of the Neanderthal people and our fear of the ‘other’ and the unfamiliar. The action is revealed through the eyes of the Neanderthals whose peaceful world is threatened by the emergence of Homo sapiens. 

The struggle between the simple Neanderthals and the malevolent modern humans ends in helpless despair ... 

From the book jacket: "When the spring came the people - what was left of them - moved back by the old paths from the sea. But this year strange things were happening, terrifying things that had never happened before. Inexplicable sounds and smells; new, unimaginable creatures half glimpsed through the leaves. What the people didn't, and perhaps never would, know, was that the day of their people was already over."

See this episode of the podcast Backlisted for an excellent discussion of the book. 

I am particularly interested in how Golding captures the perspective of pre-humans with limited cognitive abilities. He conveys the strangeness and incomprehensibility of modern humans as perceived by Neanderthals. In this sense, the book is a type of Science Fiction: it describes a first encounter with Aliens of superior capability.

We are approaching the day when modern humans will encounter a new and quasi-alien intelligence: it may be AI, or it may be genetically enhanced versions of ourselves.

On a scientific note, can someone provide an update to this 2013 work: "... high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression"? Here is an interesting follow up paper: Nature 2016 Aug 11; 536(7615): 205–209.

   

Audiobook:

 

Ghosts and Hybrids: Ancient DNA and Human Origins

Take a break from your holiday Netflix binge and learn something about recent breakthroughs in our understanding of human evolution from ancient DNA.

John Hawks (UW Madison) is an excellent speaker and this talk is for non-experts. Get the whole family together to watch -- it's a treat to learn from one of the leading researchers!

For more video of lectures at MSU, by our faculty and visitors, see this YouTube channel: https://www.youtube.com/user/msuresearch

Dr. John Hawks delivers a lecture on Ancient DNA & Human Origins at Michigan State University on October 4, 2018.

The rapidly changing field of ancient DNA has settled into a kind of normal science, as several teams of researchers have coalesced around a set of approaches to discover the genetic relationships among ancient peoples.

Hawks is the Vilas-Borghesi Distinguished Achievement Professor of Anthropology at the University of Wisconsin - Madison. He is an anthropologist and studies the bones and genes of ancient humans. He's worked on almost every part of our evolutionary story, from the very origin of our lineage among the apes up to the last 10,000 years of our history.

Frozen in time

Although we have whole genome reconstructions, we don't really know what Neanderthals looked like, exactly. It would be amazing to discover an intact individual.

National Geographic: As global warming causes ice sheets and glaciers to retreat, it will be “very, very likely” that a well-preserved Neanderthal will one day emerge, says Hiebert, much like the 40,000-year-old baby mammoth found in Siberia.

See also The Neanderthal Problem.

The Grisly Folk

H.G. Wells on the first encounters between modern humans and Neanderthals. See also The Neanderthal problem and Neanderthals dumb?

The Grisly Folk: ... But one may doubt if the first human group to come into the grisly land was clever enough to solve the problems of the new warfare. Maybe they turned southward again to the gentler regions from which they had come, and were killed by or mingled with their own brethren again. Maybe they perished altogether in that new land of the grisly folk into which they had intruded. Yet the truth may be that they even held their own and increased. If they died there were others of their kind to follow them and achieve a better fate.

That was the beginning of a nightmare age for the little children of the human tribe. They knew they were watched.

Their steps were dogged. The legends of ogres and man-eating giants that haunt the childhood of the world may descend to us from those ancient days of fear. And for the Neandertalers it was the beginning of an incessant war that could end only in extermination.

The Neandertalers, albeit not so erect and tall as men, were the heavier, stronger creatures, but they were stupid, and they went alone or in twos and threes; the menfolk were swifter, quicker-witted, and more social — when they fought they fought in combination. They lined out and surrounded and pestered and pelted their antagonists from every side. They fought the men of that grisly race as dogs might fight a bear. They shouted to one another what each should do, and the Neandertaler had no speech; he did not understand. They moved too quickly for him and fought too cunningly.

Many and obstinate were the duels and battles these two sorts of men fought for this world in that bleak age of the windy steppes, thirty or forty thousand years ago. The two races were intolerable to each other. They both wanted the eaves and the banks by the rivers where the big flints were got. They fought over the dead mammoths that had been bogged in the marshes, and over the reindeer stags that had been killed in the rutting season. When a human tribe found signs of the grisly folk near their cave and squatting place, they had perforce to track them down and kill them; their own safety and the safety of their little ones was only to be secured by that killing. The Neandertalers thought the little children of men fair game and pleasant eating. ...

Razib Khan discusses other examples from this genre.

The essential difference

This is a recent talk at NIH, which contains some unpublished results.

In the final part of the talk (you can skip there via this link), Paabo discusses the genetic variants (~30k SNPs) that are fixed in essentially all modern humans, but are not present in the Neanderthal genomes sequenced thus far. These variants are presumably responsible for the differences between Neanderthals and moderns. Paabo obviously believes that enhanced cognition is one of the main differences, and he discusses the archaeological evidence for this. He also discusses functional investigations in genetically engineered mice, and advocates for large GWAS that might identify rare humans with "back-mutations" to the Neanderthal variant. Such studies could identify phenotypical effects.

In his recent book, Paabo wrote

(p.213) ... we estimated that the total number of DNA sequence positions at which Neanderthals differed from all humans living today will be on the order of 100,000. This will represent an essentially complete answer to the question of what makes modern humans "modern," ...

(p.253) [last paragraph of the book!] ... One can imagine putting such changes into cell lines, and into mice [or monkeys] ... in order to "humanize" or "neanderthalize" biochemical pathways or intracellular structures ... One day, we may understand what set the replacement crowd [moderns] apart from their archaic contemporaries, and why, of all the primates, modern humans spread to all corners of the world and reshaped, both intentionally and unintentionally, the environment on a global scale ...

See also The genetics of humanness, The Neanderthal Problem, and Genetic engineering of monkeys using CRISPR.

Svante Paabo: Neanderthal Man

I finally got a copy of Paabo's recent book. See earlier profile in the New Yorker.

Neanderthal Man: In Search of Lost Genomes

(p.213) ... we estimated that the total number of DNA sequence positions at which Neanderthals differed from all humans living today will be on the order of 100,000. This will represent an essentially complete answer to the question of what makes modern humans "modern," ...

(p.253) [last paragraph of the book!] ... One can imagine putting such changes into cell lines, and into mice [or monkeys] ... in order to "humanize" or "neanderthalize" biochemical pathways or intracellular structures ... One day, we may understand what set the replacement crowd [moderns] apart from their archaic contemporaries, and why, of all the primates, modern humans spread to all corners of the world and reshaped, both intentionally and unintentionally, the environment on a global scale ...

The essential difference between moderns and pre-moderns is likely a qualitative increase in cognitive ability. See Neanderthals dumb?

See also The genetics of humanness, The Neanderthal Problem, and Genetic engineering of monkeys using CRISPR.

The Neanderthal Problem

Update (2020): See also The Inheritors and The Grisly Folk: H.G. Wells and William Golding on Neanderthals.

The NYTimes magazine describes efforts to resurrect extinct species such as mammoths. Let's suppose this is possible. Perhaps it will even be possible with Neanderthals, Denisovans, Homo Erectus and other pre-modern human types.

Consider the following thought experiment. Imagine thousands of Neanderthals on some privately held land in Siberia, perhaps the secret project of a reclusive billionaire oligarch.

It's very likely these Neanderthals, although able to interbreed with humans, and probably capable of speech, will be on average considerably less intelligent than humans. If I had to guess I would suppose their average adult IQ to be about 70, or -2 SD relative to modern humans. You might wonder how they could have survived for 300k+ years with such modest intelligence, but based on my experiences with 5-10 year old kids I don't think that a sub-adult level of maximum intelligence precludes the ability to form societies and function as hunter-gatherers. (Apes survive with even less cognitive ability.) I just don't think that higher developments (e.g., invention of writing) are likely for such a population. What Homo Sapiens accomplished in 50-100k years far outstrips Neanderthal accomplishments over a much longer period of time.

Modern humans differ from each other at about 1 in 1000 places in the genome, whereas a Neanderthal and a human differ at a few per 1000 places. Some subset of these additional differences cause them to be broader, more powerfully muscled, and, most likely, less intelligent. (See Neanderthals dumb?)

Now to the problem: how should we integrate these Neanderthals into modern society?

Perhaps we should not integrate them -- better to leave them alone on protected lands, to live their ''natural'' (= nasty, brutish and short?) lives. But what if some Neanderthals express the wish to join our society? How should we best help them?

I think it's likely that no amount of special education or training will allow average Neanderthals to be successful in cognitively demanding jobs. They might face significant discrimination, given their appearance.

However, let us suppose that in this future the technology exists to modify the genes which cause the cognitive gap between moderns and Neanderthals. Suppose it is possible, through genetic engineering, to modify the genomes of Neanderthal embryos, causing their brains to develop as ours do. Would it not be our moral duty to make this modification available to Neanderthal parents who want it?

Extra credit questions:

1) Is it "racist" to make the assumptions used in our hypothetical?

2) Is it also our moral duty to make similar modifications available to human parents who happen to be well below average in cognitive ability?

See also Darwin's Savages.

Neanderthals dumb?

This figure is from the Supplement (p.62) of a recent Nature paper describing a high quality genome sequence obtained from the toe of a female Neanderthal who lived in the Altai mountains in Siberia. Interestingly, copy number variation at 16p11.2 is one of the structural variants identified in a recent deCODE study as related to IQ depression; see earlier post Structural genomic variants (CNVs) affect cognition.

From the Supplement (p.62):

Of particular interest is the modern human-specific duplication on 16p11.2 which encompasses the BOLA2 gene. This locus is the breakpoint of the 16p11.2 micro-deletion, which results in developmental delay, intellectual disability, and autism5,6. We genotyped the BOLA2 gene in 675 diverse human individuals sequenced to low coverage as part of the 1000 Genome Project Phase I7 to assess the population distribution of copy numbers in homo-sapiens (Figure S8.3). While both the Altai Neandertal and Denisova individual exhibit the ancestral diploid copy number as seen in all the non-human great apes, only a single human individual exhibits this diploid copy number state.

My recollection from the earlier (less precise) Neanderthal sequences is that the number of bp differences between them and us is few per thousand. Whereas, for modern humans it's 1 per thousand with an additional +/-15% variation due to ethnicity. So, I think it's fair to say that they are qualitatively much more different from us than we (moderns) are from each other. See also The genetics of humanness.

My colleague James Lee (I note he is too modest to list his Harvard Law degree on his faculty page!) describes the current era in genomics as an "age of wonder" :-)  We can anticipate tremendous discoveries in the next decade.

The genetics of humanness

Roughly speaking, modern humans differ from chimpanzees with probability 0.01 at a particular base in the genome, from neanderthals with probability 0.003, and from each other with probability 0.001 (this final number varies by about 15% depending on ancestral population). The neanderthal research is particularly interesting in that we will eventually be able to determine the specific genetic changes that make modern humans different (smarter?) than neanderthals. Certain regions in the genome, known as HARs (Human Accelerated Regions) are conserved in mammals such as mice, dogs, chimpanzees, even neanderthals, but show rapid recent changes in humans. It's reasonable to suspect that these regions are doing interesting things ...

See also this recent paper: Analysis of Human Accelerated DNA Regions Using Archaic Hominin Genomes (PLoS).

Svante Pääbo New Yorker profile

Very nice profile of Svante Pääbo in the New Yorker. (Subscription only.)

Pääbo's father was a Nobel laureate and I think the son has a good shot as well. What impresses me most is his creativity and willingness to take on difficult projects. Video of a 2008 lecture by Pääbo.

New Yorker: ... Svante Pääbo heads the evolutionary genetics department at the Max Planck Institute for Evolutionary Anthropology, in Leipzig, Germany. At any given moment, he has at least half a dozen research efforts in progress, all attempting to solve the question of what defines us as human. Pääbo’s most ambitious project to date, which he has assembled an international consortium to assist him with, is an attempt to sequence the entire genome of the Neanderthal. The project is about halfway complete and has already yielded some unsettling results, including the news that modern humans, before doing in the Neanderthals, must have interbred with them. Once the Neanderthal genome is complete, scientists will be able to lay it gene by gene against the human genome, and see where they diverge. “I want to know what changed in fully modern humans, compared with Neanderthals, that made a difference,” Pääbo said. “What made it possible for us to build up these enormous societies, and spread around the globe.” Pääbo, who is now fifty-six, grew up in Stockholm, the product of a love affair between his mother and a married biochemist named Sune Bergström. From an early age, he was interested in old things. In the early nineteen-eighties, he was doing doctoral research on viruses when he began fantasizing about mummies. His paper on mummy DNA became the cover article in Nature magazine. Pääbo moved to the University of California at Berkeley and, later, became a professor at the University of Munich. The first Neanderthal was found in a limestone cave about forty-five miles north of Bonn, in an area known as the Neander Valley. Describes the history of Neanderthal research. Mentions 454 Life Sciences. Toward the end of 2006, Pääbo and his team reported that they had succeeded in sequencing a million base pairs of the Neanderthal genome. But later analysis revealed that the million base pairs had probably been contaminated by human DNA. Pääbo’s research eventually showed that before modern humans “replaced” the Neanderthals, they had sex with them. The liaisons produced children, who helped to people Europe, Asia, and the New World. All non-Africans carry somewhere between one and four per cent Neanderthal DNA. From the archeological records, it’s inferred that Neanderthals evolved in Europe or Western Asia and spread out from there, stopping when they reached water or some other significant obstacle. This is one of the most basic ways modern humans differ from Neanderthals and, in Pääbo’s view, also one of the most intriguing. If the defining characteristic of modern humans is a sort of Faustian restlessness, or “madness,” then, by Pääbo’s account, there must be some sort of Faustian gene.

Lunch with Razib

I had lunch with blogger and population geneticist Razib Khan today. Lunch turned into coffee which turned into hours of discussion. Razib told me he's been blogging for a decade now. See him discuss multiregional human evolution in light of recent discoveries of archaic DNA in certain human subgroups, with Michigan paleo anthropologist Milford Wolpoff:




One concrete outcome from the meeting is I've now created a twitter feed for my blog posts. See here: @hsu_steve.

More ancient DNA

Another ancient hominid (not neanderthals, perhaps one of their contemporaries, or even an earlier erectus variant) appears to have interbred with humans. About 5% of Melanesian DNA appears to come from this hominid, whereas there seems to have been little or no interbreeding with the predecessors of groups such as Europeans, East Asians or Africans. Earlier results showed that modern Eurasians can trace a few percent of their DNA to Neanderthals.

NYTimes, Nature.

So, the following are true:

1. there were wildly divergent ancient hominids (in terms of development, skull shape, physiognomy) who could and did interbreed

2. different groups of modern humans have different distributions of ancient DNA as a consequence of this interbreeding

Much more discussion by Razib at the link below.

gnxp: ... When I was a freshman at university I took a biological anthropology course. The instructor threw out a question to the class. He noted that some paleoanthropologists observed a continuity between the skulls of Australian Aborigines and some Southeast Asian erectine populations. Australian Aborigines are a very robust people, and have been less affected by the trend toward gracility which has been the norm over the past 10,000 years for most human populations. In any case, the instructor asked for a show of hands whether such a possibility should even be discussed openly. The solid majority of the class rejected an open discussion. When asked by the instructor why, many of the students who rejected an examination of the thesis argued that such a possibility opened the path to de-humanization, oppression, and was politically too sensitive. Milford Wolpoff had obviously lost the propaganda war. The students did not consider the possibility of multiregionalism where all human populations exhibited continuity, rather, they assumed that continuity hypothesized for Australian Aborigines was specific to them, and so would associate that population with the less human branches of the hominin tree.

Humans interbred with Neanderthals

The papers from Paabo's group are available at the Science web site:

Special Feature

News focus

A Draft Sequence of the Neandertal Genome

Targeted Investigation of the Neandertal Genome by Array-Based Sequence Capture.

They describe the results of a shotgun sequencing of several Neanderthal genomes, which provide strong evidence for introgression of Neanderthal DNA into the human lineage from interbreeding. From the overview:

... Substantial controversy surrounds the question of whether Neandertals interbred with modern humans. To address this question, Green et al. tested whether Neandertals are more closely related to some present-day humans than to others.* Because modern humans are believed to have originated in Africa, if Neandertals diverged from modern humans before present-day populations began to differentiate, one would expect Neandertal sequences to match sequences from non-Africans and Africans to the same extent. Unexpectedly, the researchers found that Neandertals share more genetic variants with present-day non-Africans than with Africans. These results can be explained if gene flow occurred from Neandertals into the ancestors of non-Africans.

The observation that the Neandertal genome appears as closely related to the genome of a Chinese and a Papua New Guinean individual as to the genome of a French individual is particularly surprising as there is, to date, no fossil evidence that Neandertals existed in East Asia or Papua New Guinea. Green et al. thus suggest that gene flow between Neandertals and modern humans occurred prior to the divergence of European and Asian populations. Based on comparative genomic data, as well as a mathematical model of gene flow, the authors further estimate that between 1 and 4% of the genomes of people in Eurasia may be derived from Neandertals.

... Using this comparative approach, Green et al. came up with a list of 20 candidate regions that may have been affected by positive selection in ancestral modern humans. Five of these regions contain no protein-coding genes and may thus include structural or regulatory elements. Among the remaining 15 regions, the team identified genes involved in metabolism and cognitive and cranial development, which suggests that aspects of these processes may have been functionally important for the evolution of modern humans. [This is evidence for human evolution due to selection in the time since humans diverged from Neandertals about 300ky ago.]

The presence of Neanderthal DNA in some but not all modern human populations implies divergent evolution between groups. Needless to say, this is one of the biggest scientific results in human evolutionary history in some time.

More:

... The team measured the genetic proximity of Neandertals to pairs of modern humans from different continents, first using single-nucleotide polymorphisms (SNPs), or sites in the genome where a single nucleotide differs between individuals. When they compared a Neandertal with a European and an Asian, they found that the Neandertal always shared the same amount of derived (or more recently evolved) SNPs with each of them. But when they compared a Neandertal with an African and a European, or with an African and an Asian, the Neandertal always shared more SNPs with the European or Asian than with the African. "We've shown that Neandertals are significantly more closely related to non-Africans than Africans on average," says Reich.

Even though they looked at just two Africans for this part of the study, those two have a particularly ancient, diverse heritage, so they are a good proxy for much of the genetic diversity in Africa. But sequencing additional Africans would be a good idea, says Reich.

For now, it seems Neandertals interbred with the ancestors of Europeans and Asians, but not with the ancestors of Africans. At first, "we were baffled that this affinity with Neandertals was not only in Europe and West Asia [where it was most expected], but also in Papua New Guinea" where Neandertals never set foot, says Pääbo.

See earlier post for more background.

Also see John Hawks for in-depth analysis, including the following. In earlier work (see also here), Hawks, Wang, Cochran, Harpending and Moyzis argued that the rate of human evolution has sped up in the last 10ky or so. If their estimates are correct, the amount of change in the last 10ky may be greater than what occurred over most of the 300ky since modern humans diverged from Neanderthals.

... Green and colleagues did a similar exercise, except they went looking for "selective sweeps" in the ancestors of today's' humans. These are regions of the genome that have an unusually low amount of incomplete lineage sorting with Neandertals, and therefore represent shallow genealogies for all living people. They identify 212 regions that seem to be new selected genes present in humans and not in Neandertals. This number is probably fairly close to the real number of selected changes in the ancestry of modern humans, because it includes non-coding changes that might have been selected.

Again, that's really a small number. We have roughly 200,000-300,000 years for these to have occurred on the human lineage -- after the inferred population divergence with Neandertals, but early enough that one of these selected genes could reach fixation in the expanding and dispersing human population. That makes roughly one selected substitution per 1000 years.

Which is more or less the rate that we infer by comparing humans and chimpanzees. What this means is simple: The origin of modern humans was nothing special, in adaptive terms. To the extent that we can see adaptive genetic changes, they happened at the basic long-term rate that they happened during the rest of our evolution.

Now from my perspective, this means something even more interesting. In our earlier work, we inferred a recent acceleration of human evolution from living human populations. That is a measure of the number of new selected mutations that have arisen very recently, within the last 40,000 years. And most of those happened within the past 10,000 years.

In that short time period, more than a couple thousand selected changes arose in the different human populations we surveyed. We demonstrated that this was a genuine acceleration, because it is much higher than the rate that could have occurred across human evolution, from the human-chimpanzee ancestor.

What we now know is that this is a genuine acceleration compared to the evolution of modern humans, within the last couple hundred thousand years.

Our recent evolution, after the dispersal of human populations across the world, was much faster than the evolution of Late Pleistocene populations. In adaptive terms, it is really true -- we're more different from early "modern" humans today, than they were from Neandertals. Possibly many times more different.